1. Field of the Invention
The present invention relates generally to pomegranate extracts and methods of using thereof for treating prostate cancer in a way that increases prostate specific antigen doubling time.
2. Description of the Related Art
Phytochemicals in edible plants can have cancer preventative benefits through antioxidation and via gene-nutrient interactions. Pomegranate juice has been shown to be a rich source of polyphenolic flavonoids. Pomegranate juice possesses impressive antioxidative properties due to its high flavonoids content, mainly the water soluble tannins and proanthocyanins.
Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. Biological aggressiveness of prostate cancer is directly related to tumor volume, and tumor volume is proportional to serum prostate specific antigen (PSA). Age is the most common risk factor, with nearly 70 percent of prostate cancer cases occurring in men age 65 and older. The higher a man's PSA level, the more likely it is that cancer is present. However, recent research found prostate cancer in men with PSA levels below 4.0 ng/ml. Most men with an elevated PSA test turn out not to have cancer; only 25 to 30 percent of men who have a biopsy due to elevated PSA levels actually have prostate cancer. A prostate biopsy is the main method used to further diagnose prostate cancer.
Many patients who undergo surgery or radiation therapy to treat localized prostate cancer experience an increase in PSA level after treatment. One of methods being used is measurement of PSA velocity, which is based on changes in PSA levels over time. A sharp rise in the PSA level raises the suspicion of cancer. The rate at which the PSA level is rising for patient, after radical prostatectomy or radiation therapy for localized prostate cancer, is known to correlate with aggressiveness and growth rate of the cancer thus a rapidly rising PSA is correlated with worse patient outcomes and vice-versa. In a study of untreated patients with prostatic carcinomas, patients with shorter doubling times were found with higher clinical stages and worse histological grades whereas patients with longer doubling time were found to have more favorable outcome with low grade tumors on deferred treatment. In men with prostate cancer that has been treated with combined hormone and radiation therapy, a post treatment PSA doubling time of < or =8 months is associated with worse clinical outcomes and may be an early surrogate marker for decreased survival.
Various studies described in vitro cancer chemopreventive properties, including anti-proliferative and pro-apoptotic effects, of different pomegranate compositions on various cancer cell lines. Several studies investigated effects of pomegranate compositions on prostate cancer cell lines. The Lansky et al. studies observed different pomegranate mixture on inhibition of human prostatic adenocarcinoma PC-3 invasion and proliferation across Matrigel and inhibition of phospholipase A-2 expression associated with invasive potential. The Malik et al. study described pomegranate fruit extract on inhibition of cell growth followed by apoptosis of PC-3 through modulations in the cyclin kinase inhibitor-cyclin-cyclin dependent kinase (cdk) signal transduction pathways. The Malik et al. study also described pomegranate fruit extract administration to athymic nude mice implanted with androgen-sensitive human prostatic CWR22Rv1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. The results of pomegranate in vitro antitumor activity on human prostatic cancer cell lines and in vivo xenograft of CWR22Rv1 cell only suggest possible cancer-chemopreventive as well as cancer-chemotherapeutic effects for in vivo treatment of prostate cancer in human.
The Albrecht et al. study observed in vitro antitumor activities of pomegranate extracts on cell proliferation, cell cycle distribution, apoptosis, gene regulation, and tumor growth for PC-3, human prostatic carcinoma LNCaP, and human prostatic carcinoma DU145 human cancer cell lines whereas normal prostate epithelial cells (hPrEC) were significantly less negatively affected. The Albrecht et al. study also observed potent inhibition on tumor growth for in vivo xenograft of PC-3 in athymic nude mice injected subcutaneously with pomegranate extracts. The observation of subcutaneous injection of pomegranate extract on the growth inhibition of in vivo xenograft of PC-3 in nude mice does not validate in vivo treatment of prostate cancer in human subjects because it is not known if any administration of pomegranate extract have an antitumor activity on prostate cancer in human.
In vitro tests and in vivo animal tests are necessary to evaluate potential therapeutic effect of pomegranate compositions prior to clinical evaluations. The translation of in vitro and in vivo studies from the laboratory into the clinical trial in human is necessary to obtain and validate anticancer therapeutics for efficacy and toleration as numerous human trials of anticancer drugs have not advanced to a definitive assessment of clinical efficacy in a clinical trial. Prior to the present invention, none of prior art studies have advanced pomegranate juice to a phase II trial for treating prostate cancer. The purpose of a phase II trial of a new anticancer drug is to determine whether the drug has sufficient activity against a specified type of tumor to warrant its further development.